Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

A systematic review and meta-analysis of the morbidity of efficacy endpoints and bleeding events in elderly and young patients treated with the same dose rivaroxaban.

Rivaroxaban is a new direct oral anticoagulant, and the same dose is recommended for older and young patients. However, recent real-world studies show that older patients may need dose adjustment to prevent major bleeding. At present, the evidence for dose adjustment in older patients is extremely limited with only a few reports on older atrial fibrillation patients. The aim of this study was to review the morbidity data of adverse events and bleeding events across all indications for older and young patients treated with the same dose of rivaroxaban to provide some support for dosage adjustment in older patients. The PubMed, EMBASE, ClinicalTrials, Cochrane and Web of Science databases were searched for randomized controlled trials (RCTs) published between January 1, 2005, and October 10, 2023. The primary outcomes were the morbidity of bleeding events and efficacy-related adverse events. Summary estimates were calculated using a random effects model. Eighteen RCTs were included in the qualitative analysis. The overall morbidity of primary efficacy endpoints was higher in older patients compared to the young patients (3.37% vs. 2.60%, χ2 = 5.24, p = 0.022). Similarly, a higher morbidity of bleeding was observed in older patients compared to the young patients (4.42% vs. 6.03%, χ2 = 13.22, p < 0.001). Among all indications, deep vein thrombosis, pulmonary embolism and atrial fibrillation were associated with the highest incidence of bleeding in older patients, suggesting that these patients may be most need dose adjustment. Patients older than 75 years may require extra attention to prevent bleeding. The same dose of rivaroxaban resulted in higher bleeding morbidity and morbidity of efficacy-related adverse events in older patients compared to the young patients. An individualized dose adjustment may be preferred for older patients rather than a fixed dose that fits all.

Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients with epilepsy.

Evaluation of Dose Adjustment in Patients With Renal Impairment at Muhimbili National Hospital in Tanzania.

Background: The burden of renal diseases is increasing in developing countries like Tanzania. Drug accumulation exposes patients with renal impairment to drug toxicity that may lead to adverse drug reactions, poor adherence to treatment, and increased healthcare costs. There is limited information on the appropriateness of dosage regimen adjustment for patients with renal impairment, particularly in developing countries such as Tanzania. This study aimed to investigate the appropriateness of drug dosing in hospitalized patients with renal impairment in Tanzania. Methods: This was a retrospective cross-sectional study. It was conducted between November 2019 and April 2020 amongst hospitalized patients at Muhimbili National Hospital. All enrolled patients had serum creatinine levels ≥1.2 mg/dL and taking at least one drug requiring dosage regimen adjustment. Creatinine clearance was calculated from patient serum creatinine using the Cockcroft-Gault equation. Drug dosing appropriateness was determined by comparing the current practice with tertiary references. The relationship between the patient's baseline characteristics and the rate of dosage regimen adjustment was determined using the X2 test. Univariate and multivariate logistic regression analysis evaluated the predictors of dosing adjustment. Results: Most of the enrolled patients, 269 (98.9%) had comorbidities. Of the medication orders included in the final analysis, 372 (27%) needed dosage regimen adjustment. Out of the 372 medication orders, not adjusted were 168 (45.2%), inappropriately adjusted 105 (28.2%), and appropriately adjusted were only 99 (26.6%). In this study, 212 (77.9%) patients received at least one drug with an incorrect dosage regimen. Females and those with level 4 renal impairment patients were more likely to have their doses appropriately adjusted compared to their counterparts. Conclusions: In this study, about three-quarters of the patients received at least one drug with an incorrect dosage regimen. Thus, appropriate measures such as the availability of national guidelines and clinical decision support systems for drug dosing adjustment in patients' renal impairment should be in place.

No insulin degludec dose adjustment required after aerobic exercise for people with type 1 diabetes: the ADREM study.

AIMS/HYPOTHESIS: It is generally recommended to reduce basal insulin doses after exercise to reduce the risk of post-exercise nocturnal hypoglycaemia. Based on its long t½, it is unknown whether such adjustments are required or beneficial for insulin degludec. METHODS: The ADREM study (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) was a randomised controlled, crossover study in which we compared 40% dose reduction (D40), or postponement and 20% dose reduction (D20-P), with no dose adjustment (CON) in adults with type 1 diabetes at elevated risk of hypoglycaemia, who performed a 45 min aerobic exercise test in the afternoon. All participants wore blinded continuous glucose monitors for 6 days, measuring the incidence of (nocturnal) hypoglycaemia and subsequent glucose profiles. RESULTS: We recruited 18 participants (six women, age 38 ± 13 years, HbA1c 56 ± 8 mmol/mol [7.3 ± 0.8%], mean ± SD). Time below range (i.e. glucose <3.9 mmol/l) the night after the exercise test was generally low and occurrence did not differ between the treatment regimens. During the subsequent whole day, time below range was lower for D40 compared with CON (median [IQR], 0 [0-23] vs 18 [0-55] min, p=0.043), without differences in the number of hypoglycaemic events. Time above range (i.e. glucose >10 mmol/l) was greater for D20-P vs CON (mean ± SEM, 584 ± 81 vs 364 ± 66 min, p=0.001) and D40 (385 ± 72 min, p=0.003). CONCLUSIONS/INTERPRETATION: Post-exercise adjustment of degludec does not mitigate the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Although reducing degludec reduced next-day time below range, this did not translate into fewer hypoglycaemic events, while postponing degludec should be avoided because of increased time above range. Altogether, these data do not support degludec dose adjustment after a single exercise bout. TRIAL REGISTRATION: EudraCT number 2019-004222-22 FUNDING: The study was funded by an unrestricted grant from Novo Nordisk, Denmark.

Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

BACKGROUND: Obesity (body mass index [BMI] ≥30 kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. METHODS: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). RESULTS: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90 mg/m2 ) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p = .14). CONCLUSIONS: Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

Clinical Treatment Guidelines for Tafasitamab Plus Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations.

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment.

The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug-drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease-drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47- and 0.63-fold) with notably enhanced clearance (2.00- and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43- and 1.50-fold) and clearance (0.69- and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.

Switching pattern and dose adjustment of antidepressants before and during pregnancy.

The purpose of the study is to examine the switching pattern and dose adjustment of antidepressants (ADs) prescribed to women from six months before to six months during pregnancy in the Netherlands. The recorded dispenses or refills were collected from the University of Groningen IADB.nl pregnancy subset for all singleton pregnancies in which the mother received ≥ 1 prescription of an AD dispensed before pregnancy and was present in the database at least six months after conception. The rates of continuation, discontinuation, and switching between 2001 and 2020 were assessed for the ADs studied. The mean number of Defined Daily Doses (DDDs) of the most frequently continued ADs used was calculated both before and during pregnancy, and a paired t-test was used to test for significant changes. The continuation rates for AD users, especially for SSRI and SNRI continued users, increased over time from 27% and 19% (2001-2005) to 65% and 65% (2016-2020). The switching rate between ADs remained consistently low from the start of the study (2001-2005) at 2.0% to the end of the study (2016-2020) at 2.3%. Most women who switched between antidepressants during pregnancy received a different SSRI monotherapy (85%), followed by an SNRI (6%), a TCA (4%), and an "other AD" (4%). In most cases observed, the dose adjustment for the mean DDDs during pregnancy compared to the mean DDDs before pregnancy only changed little (less than 10%). Continued use of SSRIs among singleton pregnancies doubled over the study period. The low rate of AD switching and little changes in the DDD adjustment for most AD continuers indicate that pregnant women prefer to continue their prepregnancy medication rather than switch it. Most observed findings cohere with the Dutch national guidelines for antidepressant use during pregnancy.

Population Pharmacokinetic Modeling to Inform Sertraline Dosing Optimization in Patients with Depression.

Sertraline is one of the most prescribed antidepressants, but its pharmacokinetic (PK) properties are still not completely characterized. Using nonlinear mixed-effects modeling, we examined factors influencing sertraline PK variability in outpatients with major depressive disorder. Blood samples from 53 male and female adults treated with sertraline orally were collected at a steady state. Various demographic and clinical covariates were tested by stepwise regression procedure. We found that sertraline clearance is significantly influenced by serum concentrations of its main metabolite N-desmethylsertraline, whereas clearance of N-desmethylsertraline is affected by both creatinine clearance and drug daily dose. These results were confirmed by the reduction of points dispersion in goodness-of-fit plots for their predicted versus measured concentrations and with bootstrapping analyses. This finding can serve to inform sertraline dosing optimization, especially when changes in kidney function occur in treated individuals, to prevent adverse drug reactions and maximize therapeutic benefits.

Lack of pharmacokinetic interaction between derazantinib and naringin in rats.

CONTEXT: Derazantinib-an orally bioavailable, ATP competitive, multikinase inhibitor-has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA). OBJECTIVE: This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo. MATERIALS AND METHODS: A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not). RESULTS: The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone. CONCLUSION: Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

Effectiveness of Reinduction and/or Dose Escalation of Ustekinumab in Crohn's Disease: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Patients with Crohn's disease (CD) treated with ustekinumab who experience inadequate response, or loss of response after standard induction and/or maintenance dosing may benefit from dose escalation. We conducted a systematic review and meta-analysis examining the effectiveness of reinduction and/or dose interval shortening of ustekinumab in patients with active CD despite standard induction and maintenance. METHODS: Through a systematic literature search through March 31, 2021, we identified 15 cohort studies in 925 adults with CD with inadequate response or loss of response to standard dose ustekinumab, underwent dose escalation (reinduction and/or dose interval shortening to <8 weeks), and reported rates of achieving clinical response, corticosteroid-free clinical remission, endoscopic response, and/or remission. We calculated pooled rates (with 95% confidence intervals) using random effects meta-analysis and examined factors associated with response to dose escalation through qualitative synthesis of individual studies. RESULTS: On meta-analysis, 55% of patients (95% confidence interval, 52%-58%) with inadequate response or loss of response who underwent ustekinumab dose escalation achieved clinical response, with moderate heterogeneity (I2 = 57%). Approximately 61% of patients were able to achieve endoscopic response, including 29% who achieved endoscopic remission. Dose interval shortening alone recaptured response in 57% patients. No consistent factors associated with response to dose escalation were identified on qualitative synthesis. CONCLUSION: In real word settings, ustekinumab dose escalation was effective in achieving response in patients with CD with inadequate response, or loss of response to standard dose induction and/or maintenance therapy.

Development of Physiology Based Pharmacokinetic Model to Predict the Drug Interactions of Voriconazole and Venetoclax.

PURPOSE: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. METHOD: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. RESULT: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5-9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. CONCLUSION: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability.

Kidney function and prescribed dose in middle-aged and older patients starting selective serotonin reuptake inhibitors.

PURPOSE: To avoid adverse drug reactions, dose reductions are recommended when prescribing selective serotonin reuptake inhibitors (SSRIs) to patients with impaired kidney function. The extent of this practice in routine clinical care is however unknown. We aimed to evaluate the starting and maintenance SSRI doses prescribed to patients stratified by levels of kidney function in real-world practice. METHODS: Using data from the Stockholm CREAtinine Measurements (SCREAM) project, we identified 101 409 new users of antidepressants (including 52 286 SSRI users) in the region of Stockholm during 2006-2019, who were ≥50 years of age and had a recent creatinine test taken in order to estimate glomerular filtration rate (eGFR). SSRI dose reduction was defined as a prescribed SSRI dose of ≤0.5 defined daily doses, according to current recommendations. We examined the associations between eGFR and reductions in initial dose and maintenance dose of SSRIs using logistic regression models. RESULTS: Overall, reductions in initial and maintenance dose were observed among 54.1% and 34.1% of new SSRI users. Nevertheless, about 40% of individuals with an eGFR <30 ml/min/1.73 m2 were prescribed an SSRI without dose reduction. After adjusting for age and other covariates, lower eGFR was associated with moderately higher odds of dose reduction, for both initial and maintenance dose. Compared to individuals with an eGFR of 90-104 ml/min/1.73 m2 , the adjusted odds ratios for those with an eGFR <30 ml/min/1.73 m2 were 1.18 (95% CI: 1.03, 1.36) for initial dose reduction, and 1.49 (1.29, 1.72) for maintenance dose reduction. Stratified analyses showed stronger associations between lower eGFR and SSRI dose reduction among individuals aged 50-64 years and in those receiving prescriptions from psychiatric care. CONCLUSIONS: Lower kidney function was moderately associated with a reduced SSRI dose, independently of age. Prescribing SSRIs to middle-aged and older patients should not only consider patients' age but also their kidney function.

The effect of a Clinical Decision Support System on the frequency of dose adjustments of anticancer drugs in case of renal or hepatic dysfunction.

INTRODUCTION: Dose adjustments in patients with renal or hepatic dysfunction using anticancer drugs are indicated according to guidelines. However, implementation depends on awareness of prescribing physicians. We implemented a Clinical Decision Support System (CDSS), recommending dose adjustments upon electronic prescriptions based on renal and hepatic function. The alert provides a dose adjustment proposal and recent laboratory results. Our objective was to determine the frequency of dose adjustments before and after implementation of this CDSS. METHODS: We included all first orders for patients ≥18 years treated with parenteral antineoplastic agents, for whom dosage adjustment is necessary based on renal or hepatic function between February 2018 and January 2019. This study was performed at the department of Clinical Oncology and Hematology of the Amsterdam University Medical Center. We implemented the CDSS August first. All prescriptions were prescribed according to common practice. We analyzed the orders where a dose reduction based on renal or hepatic function was indicated. RESULTS: We included 73 orders before implementation and 99 orders after implementation. Before implementation 21% of doses were reduced in line with the guidelines versus 34% after implementation (p = 0.048). For hepatic dysfunction the proportion changed from 11% to 46% p = 0.011, while there was no effect for renal dysfunction (24% vs. 26% p = 0.75). CONCLUSION: Dosages are more frequently adjusted in concordance with guidelines in patients with hepatic dysfunction who are treated with parenteral antineoplastic agents after implementation of a CDSS. The change was not seen in patients with renal dysfunction.

Cefepime Induced Neurotoxicity Following A Regimen Dose-Adjusted for Renal Function: Case Report and Review of the Literature.

Introduction: Cefepime induced neurotoxicity (CIN) is commonly associated with renal dysfunction, however CIN can occur in patients with normal renal function or renally dose-adjusted regimens. Few reports of this kind have obtained cefepime concentrations to assist in diagnosis. Patient Case: A 42-year old female with a complex past medical history was transferred to our facility with chief complaint of worsening shock and respiratory failure, and the patient was also noted to be hypernatremic, experiencing diabetic ketoacidosis (DKA), and acute kidney injury (AKI). Her DKA resolved and hypernatremia and AKI began to improve. As a result, cefepime was dose-adjusted for renal function estimated by the Cockcroft-Gault (CG) equation. Her hospital course was complicated by persistent altered mental status (AMS), preventing extubation. Cefepime was discontinued due to concern for CIN, and a concentration was obtained 13-hours after the last dose which was elevated at 49 µg/mL. Two days following cefepime discontinuation, the patient's mental status improved allowing for successful extubation. The patient remained stable and was discharged to an acute care floor and then ultimately back to home. Conclusion: CIN should be part of a wider differential diagnosis for patients experiencing encephalopathy, and inaccurate renal function estimation may be a risk factor for developing CIN. Furthermore, therapeutic drug monitoring (TDM) may serve as an important clinical tool in diagnosing and managing CIN.

Clinical pharmacogenomics in action: design, assessment and implementation of a novel pharmacogenetic panel supporting drug selection for diseases of the central nervous system (CNS).

BACKGROUND: Pharmacogenomics describes the link between gene variations (polymorphisms) and drug responses. In view of the implementation of precision medicine in personalized healthcare, pharmacogenetic tests have recently been introduced in the clinical practice. However, the translational aspects of such tests have been limited due to the lack of robust population-based evidence. MATERIALS: In this paper we present a novel pharmacogenetic panel (iDNA Genomics-PGx-CNS or PGx-CNS), consisting of 24 single nucleotide polymorphisms (SNPs) on 13 genes involved in the signaling or/and the metabolism of 28 approved drugs currently administered to treat diseases of the Central Nervous System (CNS). We have tested the PGx-CNS panel on 501 patient-derived DNA samples from a southeastern European population and applied biostatistical analyses on the pharmacogenetic associations involving drug selection, dosing and the risk of adverse drug events (ADEs). RESULTS: Results reveal the occurrences of each SNP in the sample and a strong correlation with the European population. Nonlinear principal component analysis strongly indicates co-occurrences of certain variants. The metabolization efficiency (poor, intermediate, extensive, ultra-rapid) and the frequency of clinical useful pharmacogenetic, associations in the population (drug relevance), are also described, along with four exemplar clinical cases illustrating the strong potential of the PGx-CNS panel, as a companion diagnostic assay. It is noted that pharmacogenetic associations involving copy number variations (CNVs) or the HLA gene were not included in this analysis. CONCLUSIONS: Overall, results illustrate that the PGx-CNS panel is a valuable tool supporting therapeutic medical decisions, urging its broad clinical implementation.

Principles of Kidney Pharmacotherapy for the Nephrologist: Core Curriculum 2021.

Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents.

Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007-2017).

BACKGROUND: Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. METHODS: We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used. RESULTS: Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. CONCLUSIONS: This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

A phase II study of first-line afatinib for patients aged ≥75 years with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan Study Group trial NEJ027.

BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).